p21+TREM2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease
Year: 2026
Type: article
Abstract: Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether macrophages can adopt a senescent state remains unclear. Here we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging, using primary mouse and human macrophage models of DNA damage and cholesterol-induced senescence characterized by multi-omic profiling. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and senescence-associated secretory phenotype, driven in part by type I interferon signaling via cytosolic mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aging, metabolic dysfunction-associated steatotic liver disease mouse livers, and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged mice and mice with metabolic dysfunction-associated steatotic liver disease. These findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, and a tractable therapeutic target.
Source: Nature Aging
Authors: Ivan A. Salladay-Perez, Itzetl Avila, Lizeth Estrada, Andreea C. Alexandru, Cristian Ponce, Anika Dhingra, Grasiela Torres, Christina Y. Deng, Ronak Hegde, Julia Gensheimer, Abhijit Kale, Indra Heckenbach, Simon Hui, Chantle Edillor, Jose A. Soto, Alexander J. Napior, Isaiah Little, Mark Larsen, Jacob Rose, Lia Farahi, Edwin D. J. Lopez Gonzalez, Matthew R. Krieger, Kushan Chowdhury, Mridul Sharma, Yuming Jiang, Kevin Williams, Morten Scheibye-Knudsen, Carla M. Koehler, Jesse G. Meyer, Julia J. Mack, Charles Brenner, Steven J. Bensinger, Cyril Lagger, João Pedro de Magalhães, Birgit Schilling, Rajat Singh, Eric Verdin, Aldons J. Lusis, Anthony J. Covarrubias
Institutions: University of California, Los Angeles, Buck Institute for Research on Aging, University of Copenhagen, City Of Hope National Medical Center, City of Hope, Beckman Research Institute, Cedars-Sinai Medical Center, UCLA Jonsson Comprehensive Cancer Center, Kyiv School of Economics, University of Birmingham
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: American Federation for Aging Research, American Heart Association, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources
Awards: G121460750, G1406153456, G1657637021, G1689835210, G2486895776, G297113894, UCLA-Caltech Medical Scientist Training Program, G6280938746, REGULATION OF MRNA ACCUMULATION DURING EARLY DEVELOPMENT, Flow Dependent Endothelial Cell Polarization, G718837903, G7476499241, G8119508109, TripleTOF 5600 High Resolution Mass Spectrometer, Systems Genetics Dissection of Non-alcoholic Steatohepatitis, Democratizing Multi-Omics to Expedite Discovery of Hidden Metabolic Pathways, BIOGENESIS OF THE MITOCHONDRIAL INNER MEMBRANE, UCLA LIFT-UP (Leveraging Institutional support For Talented, Upcoming Physicians and/or Scientists), Diabetes Research Center (DRC), Exploring the fundamental cellular mechanisms driving cellular senescence in macrophages, Research Training in Cell and Molecular Biology, Tumor Cell Biology Training Program
OpenAlex ID: W7154570070